Macrocyclic compounds for modulating IL-17

A compound represented by Formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from —O— and —N((C0-C3 alkylene)-Q)-, wherein
• Q is selected from hydrogen, —N(R7e), —OH, —O—C1-C4 alkyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl;
• the alkylene portion of R1, if present, is optionally substituted;
• and
• when the —C(O)— group adjacent to R1 is bound directly to an —N(R7h)— in R3, R1 is additionally selected from —CH2—;
• R2 is an optionally substituted C3-C12 alkylene, optionally substituted C3-C12 alkenylene, or optionally substituted C3-C12 alkynylene, wherein:
• up to three methylene units of R2 are optionally and independently replaced with —O—, —N(Rc)—, —S—, —S(O)—, or —S(O)2—, wherein
• Rc is selected from hydrogen, C1-C4 alkyl, —C(O)—C1-C3 alkyl, —C(O)—(C1-C3 alkylene)-aryl, —C(O)—(C1-C3 alkylene)-heteroaryl, —C(O)—O—C1-C3 alkyl, —C(O)—O—C1-C3 alkenyl, —S(O)2—C1-C3 alkyl, —S(O)2—(C1-C3 alkylene)-aryl, and —S(O)2—(C1-C3 alkylene)-heteroaryl;
• or
• when R1 is —N((C0-C3 alkylene)-Q)-, Rc is optionally taken together with R1 and any intervening atoms to form a heterocyclyl;
• any two substituents bound to a common carbon atom in R2 are optionally taken together to form ═O, carbocyclyl, or heterocyclyl;
• any two substituents bound to different carbon atoms in R2 are optionally taken together with any intervening atoms to form an aryl, heteroaryl, carbocyclyl, or heterocyclyl;
• any two Rc are optionally taken together with the nitrogen atoms to which they are bound and any intervening atoms to form a heterocyclyl;
• and
• any substituent bound to a carbon atom in R2 is optionally taken together with any one Rc or with R7a and any intervening atoms to form heteroaryl or heterocyclyl;
• R3 is —[C(Rd)(Rd)]p—[N(R7h)]0-1—[C(Rd)(Rd)]q—, wherein:
• each Rd is independently selected from hydrogen and a suitable alkylene substituent;
• and any two Rd are optionally taken together with any intervening atoms to form aryl, heteroaryl, carbocyclyl, or heterocyclyl;
• p is 0, 1 or 2;
• q is 0, 1 or 2;
• and
• p+q is 2 or more;
• R4 is —[C(Re)(Re)]n—Y—[C(Re)(Re)]m—, wherein:
• each Re is independently selected from hydrogen and a suitable alkylene substituent;
• Y is selected from aryl, heteroaryl, carbocyclyl, heterocyclyl, and optionally substituted C1-C3 alkylene;
• each of n and m are independently selected from 0, 1, 2, 3, 4, 5, and 6;
• and
• n+m is 6 or less;
• R5 is C1-C2 alkylene substituted with one or more —(C0-C5 alkylene)-Rf, wherein each Rf is independently selected from —CH3, —O—C1-C3 alkyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl;
• R6 is selected from heteroaryl, —CH2-aryl, —C(O)—R8, —C(O)—O—R8, —C(O)—C(O)—R8, —S(O)—R8, —S(O)2—R8, C(O)—N(R7f)—R8, and —S(O)2—N(R7f)—R8;
• each R7a, R7b, R7c, R7d, R7e, R7f, and R7g is independently selected from hydrogen and C1-C4 alkyl;
• R7h is independently selected from hydrogen, C1-C4 alkyl, phenyl, and benzyl;
• R8 is selected from —(C0-C6 alkylene)-aryl, —(C0-C6 alkylene)-heteroaryl, —(C0-C6 alkylene)-carbocyclyl, —(C0-C6 alkylene)-heterocyclyl, and C1-C6 alkyl, wherein
• when R8 is C1-C6 alkyl, up to two methylene units in the alkyl are optionally and independently replaced with —O—, —N(R7g)—, —S—, —S(O)—, or —S(O)2—;
• and
• any alkyl or alkylene portion of R8 is optionally substituted with an appropriate alkyl or alkylene substituent other than ═O;
• or
• R7d and R6 are optionally taken together to form a heterocyclyl;
• and
• any aryl, heteroaryl, carbocyclyl, or heterocyclyl portion of the compound is optionally substituted.